New Tests and Treatments for Dyspepsia and Irritable Bowel Syndrome

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1 New Tests and Treatments for Dyspepsia and Irritable Bowel Syndrome Soojong Hong Chae, MD Clinical Assistant Professor Digestive Diseases and Nutrition University of South Florida ROME III Functional dyspepsia are symptoms that are thought to originate in the gastroduodenal region early satiation postprandial fullness epigastric pain burning IBS is characterized by abdominal pain and discomfort in association with altered bowel habits

2 Functional Dyspepsia Moayyadi P. Curr Opin Gastroenterol 2012, 28: Irritable Bowel Syndrome Ford A. Clin Gastroenterol Hepatol 2012;10

3 FD Pathophysiology Rapid or delayed gastric emptying Impaired gastric accommodation Hypersensitivity to gastric distention Altered response to duodenal lipids or acid H. Pylori infection Abnormal duodenojejunal motility Central nervous system dysfunction Tack, J. Gastroenterology 2004;127: IBS Physiologic Features Altered motility Visceral hyperalgesia Disturbance of brain-gut interaction Abnormal central processing Autonomic and hormonal events Intestinal microbiota Psychosocial disturbance

4 Subcategories of FD Post-prandial distress syndrome (PDS) Postprandial fullness and early satiation Respond to prokinetic agent Epigastric pain syndrome (EPS) Epigastric pain and burning Respond acid suppressive therapy Major overlap between PDS and EPS Gastroenterology 2006;130: Categories of IBS Diarrhea-predominant IBS (IBS-D) Loose (mushy) or watery stools > 25% of BMs Hard or lumpy stools < 25% BMs Constipation-predominant IBS (IBS-C) hard or lumpy stools > 25% of BMs loose (mushy) or watery stools < 25% BMs Mixed IBS (IBS-M) hard or lumpy stools > 25% of BMs loose (mushy) or watery stools > 25% of BMs Unsubtyped IBS

5 Normal Gastric Function Tack, J. Gastroenterology 2004;127: Functional Dyspepsia 30% of patients have delayed gastric emptying 10% have accelerated gastric emptying 40% have impaired gastric accommodation 30% have evidence of hypersensitivity to gastric distention Tack J. Curr Opin Gastroenterol 2011; 27: Bredenoord AJ. Clin Gastroenterol Hepatol 2003;1:264 72

6 Colonic Transit Time in IBS Simren M. Am J Gastroenterol 2012; 107: Small Intestinal Bacterial Overgrowth (SIBO) Defined as 10 5 or more colony-forming units of colonic bacteria per milliliter Upper small intestinal tract is relatively sterile environment Normal peristalsis Antibacterial action of gastric acid Diarrhea, constipation, bloating, gas, abdominal pain, B12 deficiency

7 IBS and SIBO overlap 78% (157/202) of IBS patients were positive for SIBO by lactulose breath test 47 patients were retested after abx rx 25/47 had eradication of SIBO 48% of eradicated group no longer met IBS criteria Pimentel, M. Am J Gastro. 2000;95: IBS pts and 26 controls Posserud. Gut. 2007;56:

8 IBS and SIBO overlap 4% IBS were found to have SIBO by jejunal cultures Similar proportions of positive LHBT and GHBT in IBS vs control Did not confirm strong association between IBS and SIBO Posserud. Gut. 2007;56: New Diagnostic Tests FD and IBS Disordered motility leading to altered transit and altered stool form Transit studies Altered intestinal microbiota Hydrogen breath test

SmartPill Senses and measures temperature, ph and pressure Wirelessly transmits data to

9 Wireless Motility Capsule : SmartPill FDA approved ingestible capsule using sensor technology to evaluate GI motility Receiver Display software Wireless Motility Capsule : SmartPill Senses and measures temperature, ph and pressure Wirelessly transmits data to receiver Battery life 5+ days 26 mm x 13 mm TRANSMITTER PRESSURE SENSOR BATTERIES ph SENSOR MICROPROCESSOR

Overnight fast Patient Information List of medications to avoid Ingests 260 kcal SmartBar and then SmartPill Wears data receiver and goes about normal daily activities Return data receiver 3-5 days

10 Overnight fast Patient Information List of medications to avoid Ingests 260 kcal SmartBar and then SmartPill Wears data receiver and goes about normal daily activities Return data receiver 3-5 days later Medications that alter ph Proton pump inhibitors Histamine receptor antagonist Antacids Medications that alter motility Prokinetics (metoclopromide, domperidone, erythromycin, azithromycin) Antiemetics Anticholinergics (dicyclomine, hyoscyamine) Laxatives Antidiarrheals Narcotics NSAIDS Time period of medication discontinuation 7 days 3 days 1 day Time period of medication discontinuation 3 days 3 days 3 days 2 days 3 days 3 days 3 days

Contraindications Dysphagia Suspected strictures or fistulae Pseudo-obstruction, ileus, gastric bezoar GI surgery within the past 3 months Diverticulitis Electromechanical

11 Contraindications Dysphagia Suspected strictures or fistulae Pseudo-obstruction, ileus, gastric bezoar GI surgery within the past 3 months Diverticulitis Electromechanical medical device Pacemaker or infusion pump Not approved in children Wireless Motility Capsule Tracing Gastric Transit Small Bowel Transit Colonic Transit ph Temperature Pressure

12 Gastric Emptying Time (GET) GET : abrupt rise in ph (3 ph units) Validation of Gastric Emptying Time 87 healthy adults and 61 gastroparesis Simultaneous WMC & gastric emptying scintigraphy Sensitivity Specificity GES 2 h 34% 93% GES 4 h 44% 93% GET 65% 87% Kuo B, et al. Aliment Pharmacol Ther. 2008; 27:

Small Bowel Emptying Time (SBTT) SBTT : sustained (>10 minutes) drop in ph (1 ph unit) 10 healthy adults Validation of SBTT Simultaneous WMC and whole gut scintigraphy

13 Small Bowel Emptying Time (SBTT) SBTT : sustained (>10 minutes) drop in ph (1 ph unit) 10 healthy adults Validation of SBTT Simultaneous WMC and whole gut scintigraphy Comparable SBTT between 2 methods There are no prospective studies SBTT in diseased states intestinal pseudo obstruction Maqbool S et al. Dig Dis Sci. 2009l54:

14 Colonic Transit Time (CTT) CTT : loss of recording signal or abrupt decrease in temperature Validation for CTT 78 adults Rome II functional constipation and 87 healthy adults WMC vs 2 day and 5 day ROM Sensitivity Specificity SmartPill CTT 46% 95% WGTT 42% 95% Day 5 ROM 37% 95% Rao SS et al. Clin Gastro Heaptol. 2009;7:

15 Delayed Gastric and Colonic Transit

16 Hydrogen Breath Test Breath tests based on bacterial production of hydrogen and methane after metabolizing substrate Lactulose Glucose Xylose Breath Tests Hydrogen and Methane gas measured every 30 minutes for 3 hours Rise of Hydrogen 12 or 20 ppm above baseline is considered diagnostic Rise of Methane 20 ppm above baseline Wide variation in sensitivity and specificity

Lactulose Breath Test Lactulose not absorbed by small intestine Cleaved by bacteria in proximal colon into hydrogen In bacterial overgrowth, early hydrogen peak is observed 60-90 min Double peak Slow

17 Lactulose Breath Test Lactulose not absorbed by small intestine Cleaved by bacteria in proximal colon into hydrogen In bacterial overgrowth, early hydrogen peak is observed min Double peak Slow and rapid small intestinal transit may affect test results Lactulose accelerates transit Sensitivity of 68% and specificity of 44% Kassinen A. Gastroenterology 2007;133:24e33. Simren M. Gut 2013;62:

18 Glucose Breath Test Normally glucose is entirely absorbed in proximal jejunum In bacterial overgrowth, glucose cleaved into carbon dioxide and hydrogen If positive, most likely SIBO If negative, may be missing distal SIBO Largest study, sensitivity of 62% and specificity of 83% Treatment

19 New Treatments FD Buspirone (5-HT 1A agonist) Superior to placebo in alleviating symptoms Early satiation, postprandial fullness and upper abdominal bloating Symptom improvement was associated with delay in liquid gastric emptying rate and an increase in meal-induced gastric accommodation Tandospirone (5-HT 1A agonist) Study in Japan Tack J. Clin Gastro and Hep 2012;10: Miwa H. Am J Gastroenterol 2009;104: Buspirone Tack J. Clin Gastro and Hep 2012;10:

20 Tack J. Clin Gastro and Hep 2012;10: New treatments for FD Acotiamide (Z-338) Enhances acetylcholine release via antagonism of the M1 and M2 muscarinic receptors Enhance gastric accommodation in animal studies Indirect effect on brain gut axis Does not prolong QT interval Suzuki H, Hibi T. Neurogastroenterol Motil 2010; 22: Tack J, Janssen P. Expert Opin Investig Drugs 2011; 20: Matsueda K. Gut Jun;61(6):821-8

21 Acotiamide 4-week placebo-controlled Phase III study in PDS in Japan Relieving postprandial fullness, early satiation and upper abdominal bloating Matsueda K. Gut Jun;61(6):821-8 Acotiamide : Overall Treatment Efficacy (OTE) Matsueda K. Gut Jun;61(6):821-8

22 Linaclotide Chey WD. Am J Gastroenterol. 2012

23 Linaclotide IBS C : 290 mcg daily 30 minutes prior to first meal CIC : 145 mcg daily 30 minutes prior to first meal Capsules should be swallowed whole and should not be broken apart or chewed Diarrhea was the most common (20%) adverse reaction TARGET I & TARGET II Multi-center, Phase III RCT. Enrolled 1260 non-c IBS patients Demographic data: mean age 45, 75% women, 90% white, 10% >65 yo Pimentel M. N Engl J Med (1):22-32

Study Design Rifaximin 550 mg TID vs Placebo for 14 days Follow up for 10 weeks Primary endpoint adequate relief of IBS symptoms Secondary endpoint adequate relief of bloating

24 Study Design Rifaximin 550 mg TID vs Placebo for 14 days Follow up for 10 weeks Primary endpoint adequate relief of IBS symptoms Secondary endpoint adequate relief of bloating Pimentel M. N Engl J Med (1):22-32 Results p = p = p = Percent Responders Pimentel M. N Engl J Med (1):22-32

25 Overall improvement of global IBS symptoms with Rifaximin during 10 weeks of follow up Pimentel M. N Engl J Med (1):22-32 Mechanism of Action Reduction of overall bacterial load Decreased bacterial fermentation Less bloating Effect on intestinal microbiota might alter local mucosal engagement of bacteria such as the immune response of host Not FDA approved for the treatment of IBS

Modulation of Intestinal Microbiota A short course of non-absorbable antibiotic such as Rifaximin in IBS-D Improves bloating and flatulence Majority of trials of probiotics in IBS show some degree of

26 Modulation of Intestinal Microbiota A short course of non-absorbable antibiotic such as Rifaximin in IBS-D Improves bloating and flatulence Majority of trials of probiotics in IBS show some degree of efficacy Prebiotics and synbiotics should theoretically have the potential in treating FGD FODMAP Fermentable oligosaccharides, disaccharides, monosaccharides and polyols Poorly absorbed, shortchain carbohydrates, highly fermentable in presence of gut bacteria

27 FODMAP Fructans and Galactans Fructose Lactose Fructooligosaccharide Galactooligosaccharide Polyols Sorbitol Xylitol Mannitol Maltitol

28 FODMAP 26 Australian IBS pts with positive fructose breath tests Provided low FODMAP diet up to 22 wks Randomized 4 groups Fructose, fructan, fructose and fructan and glucose powder mixed in water Primary end point was were symptoms adequately controlled during the phase Shepherd SJ, Clin Gastro Hep, 2008:6; FODMAP Shepherd SJ, Clin Gastro Hep, 2008:6;

29 FODMAP : Practical Guidelines Hydrogen breath testing if readily available as this could potentially limit what foods need to be restricted. Referral to a dietitian who is comfortable with the low FODMAP approach Complete FODMAP restriction for 6 weeks. A slow controlled reintroduction of FODMAPs to determine the level that will be tolerated Summary Newer diagnostic tests Wireless motility capsule Hydrogen breath test Newer treatments for functional dyspepsia Buspirone, Tandospirone Acotiamide Newer treatments for IBS Linaclotide Rifaximin Probiotics Low FODMAP diet

Outline. Definition (s) Epidemiology Pathophysiology Management With an emphasis on recent developments

Outline. Definition (s) Epidemiology Pathophysiology Management With an emphasis on recent developments Chronic Dyspepsia Eamonn M M Quigley MD FRCP FACP MACG FRCPI Lynda K and David M Underwood Center for Digestive Disorders Houston Methodist Hospital Houston, Texas Outline Definition (s) Epidemiology Pathophysiology